Recent genome-wide studies suggest that long non-coding RNAs (nc-RNAs) have potential as regulators of gene expression. BGLT3, a non-coding RNA transcript located 2,000 bp downstream of the A-gamma-globin gene, harbors an LDB1 complex binding site that is involved in LCR looping. We have shown that the BGLT3 gene interacts with the gamma-globin gene promoter and the upstream LCR region and that expression of BGLT3 parallels that of the gamma-globin genes. We used 5and 3RACE to map the ends of BGLT3, knocked down BGLT3 expression using anti-sense oligonucleotides and over-expressed BGLT3 in both the WT and BGLT3-reduced background. Finally, we directed a catalytically inactive Cas9 (dCas9) to the 5 end of the BGL3 gene to block the transcript. These experiments showed that both the BGLT3 transcript and the locus are required for gamma-globin transcription. Chromatin capture (3C) experiments revealed that the interaction of the gamma globin genes with the LCR was not affected in the BGLT3 null cells. However, the interaction between the gamma genes and BGLT3 itself was strongly reduced in the BGLT3 null mutants. Thus, the BGLT3-gamma-globin interaction contributes to gamma-globin expression separately from interaction of the gene with the LCR. The Myb proto-oncogene encodes the transcription factor c-Myb which is known to play a role in the proliferation and differentiation of all hematopoietic stem and progenitor cells. This gene is activated by a series of LDB1-occupied enhancers that make complex interactions with the gene. We identified a new long non-coding RNA (lncRNA) originating from the -81kb enhancer within the Myb & Hbs1l intergenic region. Using CRISPR/Cas9 genome editing, we showed that reduction of the lncRNA expression by a 17-nucleotide deletion in the -81kb enhancer caused inactivation of Myb gene expression. Utilizing ChIP and chromosome conformation capture (3C) assays, we found that depletion of the lncRNA negatively affected long-range interactions between the Myb gene promoter and its intergenic enhancers without changing LDB1 complex occupancy or H3K27ac histone modification at the enhancers. Additionally, RNA immunoprecipitation experiments suggest that the lncRNA is a part of the LDB1 complex. We conclude that expression of the Myb gene is regulated, at least in part, by the -81 kb enhancer-derived lncRNA through facilitating LDB1-dependent enhancer-gene interactions. Although a large number of lncRNAs have been discovered by high throughput sequencing, their functions are still mostly unknown. Given that many lncRNAs are associated with cell fate determination and commonly regulate neighboring genes, we screened several lncRNAs around core transcription factors that control erythroid differentiation by lentivirus-mediated stable knockdown in K562 cells. Using RT-qPCR and flowcytometry, we found that knockdown of two lncRNAs, GATA2AS and lncPPRC1, could significantly decrease expression of their neighboring genes GATA2 and LDB1, respectively. We also found the expression levels of these two lncRNAs expression levels were positively correlated with GATA2 and LDB1 expression during erythroid differentiation. In the hemin- induced K562 differentiation model, we found that knockdown of GATA2AS andl LncPPRC1 impairs gamma globin gene activation. Taken together, these results suggest lncRNA GATA2AS and lncPPRC1 may be involve in erythroid differentiation by regulating GATA2 and LDB1. The influence of epigenetic proteins and modifications on enhancer-promoter long range interactions to activate gene expression is mostly unknown. To address this issue, we have undertaken a genome wide CRISPR/Cas9-mediated knock out screen for epigenetic modifications essential for mediating enhancer-promoter communication during terminal differentiation of a mouse erythroleukemia (MEL) cell line. To easily track expression of the adult beta-globin gene, we have created a reporter cell line via a CRISPR/Cas9 mediated knock-in strategy that introduced GFP into the 3UTR. Prior to conducting the screen, we tested the approach by conducting a small drug screen for epigenetic factors that affect beta-globin activation during terminal differentiation. We identified several compounds that potently reduced beta-globin activation in a dose-dependent fashion without significantly affecting cell viability. Given that many of these drugs inhibit transcriptional repressors, we hypothesize that these drugs exert their effects not directly though the alteration of the beta-globin locus itself, but rather via altered expression of upstream regulators. Future work will further elucidate the role these critical epigenetic enzymes during erythropoiesis.